The HIV lipodystrophy syndrome is a recognized complication of highly active antiretroviral therapy (HAART) that is characterized by fat redistribution and insulin resistance. Studies using 1H-magnetic resonance spectroscopy (1H-MRS) have shown strong correlation of insulin resistance with concentrations of intramyocellular lipids (IMCL) in patients with type 2 diabetes, obesity, and HIV-lipodystrophy syndrome. However, very few studies have investigated IMCL overaccumulation as a potential mechanism of insulin resistance in HIV-positive patients, and the ability of IMCL to predict insulin resistance compared to detailed measures of insulin dynamics and body-composition. Furthermore, the effect of HAART and lipolytic blockade on muscle lipid metabolism remains unknown. Investigation of mechanisms and surrogate markers of insulin resistance is critical in patients with HIV infection to guide preventive strategies for long-term increased cardiovascular risk. My first hypothesis is that IMCL are increased among insulin resistant, HIV- infected patients with the lipodystrophy syndrome, and IMCL correlates strongly with sensitive indices of fat redistribution and insulin resistance. We will quantify IMCL using 1H-MRS in HIV-infected patients with and without lipodystrophy and healthy controls, and examine relationships with detailed measures of body composition, insulin dynamics and glucose homeostasis. My second hypothesis is that lipid accumulation occurs prior to development of overt insulin resistance and is a critical pathophysiological component of the development of insulin resistance in HIV-infected patients. IMCL levels will be determined with 1H-MRS before and after initiation of HAART in acute and chronic therapy-na'fve HIV-infected patients. My third hypothesis is that chronic lipolytic blockade with Acipimox will decrease fat accumulation in muscle and improve insulin resistance in HIV-infected patients with lipodystrophy syndrome. We will measure IMCL levels during chronic therapy with Acipimox and examine relationships with dyslipidemia, insulin resistance and lipolysis rate. In summary, this proposal will utilize 1H-MRS as a novel technique to investigate metabolic changes of muscle in the HIV-lipodystrophy syndrome and determine the role of IMCL in the pathogenesis of insulin resistance in this population, in addition, the natural history of IMCL will be followed in HIV-infected patients before and after the introduction of HAART and during chronic lipolytic blockade.